The development of substance use disorder (SUD) during adolescence is a major public health problem which not only relates to the younger population, but also for the long-term mental health of adults. SUD often co-occurs with depression in adolescents and in some youth, depression may be a precursor to SUD. Comorbid depression and SUD is associated with significant added psychosocial and economic burden, thus highlighting the need to identify factors that increase the risk for these disorders. Several lines of investigation suggest hypotheses for examining the associations among depression, SUD, psychosocial stress and hypothalamic-pituitary-adrenal (HPA) system. In support of this hypothesis, in two preliminary studies, we have shown that elevated cortisol, or high level of life stress, is associated with increased risk for SUD in depressed youth. Using a longitudinal design, this investigation aims to examine the risk for development of SUD in depressed adolescents by recruiting youth before they develop these problems. The study also aims to evaluate the association between HPA dysregulation and risk for SUD in this cohort. The contribution of psychosocial stress in predicting risk for SUD will be assessed in those with and without HPA dysregulation. In addition to estimating the magnitude of risk for SUD in those with HPA dysregulation and/or psychosocial stress, factors that confer protection against SUD in such vulnerable individuals will be identified. The project is also designed to assess the effects of SUD on clinical course of depression and on social adjustment. If our initial results, showing a relationship between high cortisol and risk for SUD, are replicated in a larger sample of depressed adolescents, the findings potentially might be helpful in identifying the subgroup of youth who might benefit most from antidepressant or anti-glucocorticoid treatment strategies. Evidence suggests that a good response to antidepressant agents may be due to the down-regulation of the HPA axis. If stress contributes to the risk for SUD in some depressed youth, they might benefit from adjunctive psychosocial interventions. More focused and effective treatments potentially might be helpful in reducing the risk for SUD in depressed youth. Moreover, such treatment strategies can be extended for testing in non-depressed youth.